Emerging evidence suggests that, contrary to previous assumptions, not all cells of the human body have an identical DNA sequence, a phenomenon known as somatic variation. Somatic variations have been shown to cause cancer and several other diseases, but the extent of this phenomenon in the human body remains unknown, in part because somatic mutations often occur in a small proportion of cells and may not be detected in the whole population. Therefore, studying this phenomenon has fundamental importance to our understanding of how the human body functions, what causes/predisposes us to various diseases, and how we can avoid and/or cure them. This proposal describes the development of computation methods and experimental approaches for the analysis of single cell's genomes, as well as how to apply these methods and approaches to study somatic mosaicism in human skin fibroblasts. The proposal first suggests developing a sophisticated, comprehensive approach for somatic variation discovery based on single cell clonal expansion. Then, this approach will be applied to uncover somatic mosaicism in human skin fibroblasts cells and will result in a reference set of somatic variants in this tissue. The result of completig the project will be new computational and experimental analytical approaches for single cell sequencing analysis. These approaches can be used in various single cell studies (somatic mosacism, organism development, etc.) and in the clinic (e.g., for cancer monitoring). Moreover, the result will provide a better understanding of genome variations in human body, which ultimately is relevant in: i) understanding and preventing the susceptibility of different people t different diseases; i) estimating the effectiveness of different treatments for each particular person; and, iii) creating the foundation for personalized medicine.